The design of novel structures, based on the binding site with, which the ligand needs to interact, is involved in de novo drug design. Earlier, the de novo drug design was carried out manually. Automated drug design was introduced only later on.
In automated drug design, a large number of diverse structures can be produced at a faster rate and in a short time period. The structure I and II are suitable structures for the de novo drug design. However, Structure I seems to be less rigid than that of structure II.
Since, the structure II is a rigid structure; it is expected to bind more efficiently, as per the binding theory. This rigid structure is locked into the active conformation that is required for the binding site. On the contrary, in the de novo drug design technique, the rigid structure may not bind as expected.
Thus, the flexible molecules are considered better in this drug design technique than the rigid structure, in order to test the binding theory. This is because the rigid molecules may fail to bind as predicted, unlike flexible molecules, which may undergo conformational alternations or changes, so as to bind with the molecule as expected.
There is still a good chance if the molecule does not bind as expected. It could use an alternative binding mode by changing its configuration or structure. It would be advantageous as it can provide the beneficial information about the actual binding and this in turn, results in designing a drug on the basis of the binding structure. Using structure II for testing the binding theory would not have been equally beneficial.